Bone marrow transplantation has the potential of providing a complete cure of the disease symptoms of hemoglobinopathies. Successful application of mismatched (related-haploidentical) bone marrow transplantation to patients with sickle cell disease or thalassemia requires that allochimerism be achieved and stabilized in the bone marrow with less morbidity and mortality than is being experienced in existing mismatched bone marrow transplantation (BMT) protocols. This goal requires use of less total body radiation and less drug myeloablation in support of the transplantation. Mixed chimeric bone marrow states have been achieved and stabilized in mice through the use of psoralen photochemically treated donor leukocytes which are blocked in their proliferative capabilities but which retain their immunological activities. Model mouse bone marrow transplantation experiments, in a complete MHC mismatch setting, have recently demonstrated that under low dose myeloablative radiation conditions and in the absence of myeloablative and immunosuppressive drugs, S-59 (a psoralen) photochemically treated (S-59 PCT) T-cell add-backs promote and stabilize allochimerism with greatly reduced risk of graft versus host disease (GVHD). With the completion of this validation through the support of US Public Health Service Grant R01 HL63456, "Stem Cell Transplantation to Establish Allochimerism," this project is now entering a development phase that should ultimately lead to an approved clinical protocol of pediatric allogeneic stem cell transplantation. This success has resulted from a very productive collaboration between Children's Hospital Oakland Research Institute and Cerus Corporation. Because cord blood has recently become an important source of stem cells for pediatric marrow transplant, we have designed a cord blood study in mice that will test the value of PCT T-cell supplements in the improvement of safety in cord blood transplantation. The objective of such a study is to provide pre-clinical support for a clinical trial for pediatric patients with sickle cell disease or thalassemia. In this application, we propose to validate cord blood transplantation in a mouse model and to determine the value provided by T-cell depletion and Amotosalen photochemically treated T-cell supplements in providing a safer alternative to conventional cord blood stem cell transplantation (which does not include PCT T-cell supplements).